Methods and apparatus for multi-vessel renal neuromodulation

ABSTRACT

Methods and apparatus are provided for multi-vessel neuromodulation, e.g., via a pulsed electric field. Such multi-vessel neuromodulation may effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential attenuation or blockade, changes in cytokine up-regulation and other conditions in target neural fibers. In some embodiments, the multi-vessel neuromodulation is applied to neural fibers that contribute to renal function. Such multi-vessel neuromodulation optionally may be performed bilaterally.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/966,897, filed Dec. 13, 2010, which is a continuation ofU.S. patent application Ser. No. 11/451,728, filed Jun. 12, 2006, nowU.S. Pat. No. 7,853,333, which is a continuation-in-part of U.S. patentapplication Ser. No. 11/129,765, filed May 13, 2005, now U.S. Pat. No.7,653,438, which claims the benefit of U.S. Provisional Application Nos.(a) 60/616,254, filed on Oct. 5, 2004, and (b) 60/624,793, filed on Nov.2, 2004.

All of these applications are incorporated herein by reference in theirentireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. In some embodiments, the present invention relates tomethods and apparatus for achieving renal neuromodulation.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes altered,which results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Chronic Renal Failure (“CRF”),End-Stage Renal Disease (“ESRD”), hypertension (pathologically highblood pressure) and other cardio-renal diseases. The functions of thekidneys can be summarized under three broad categories: filtering bloodand excreting waste products generated by the body's metabolism;regulating salt, water, electrolyte and acid-base balance; and secretinghormones to maintain vital organ blood flow. Without properlyfunctioning kidneys, a patient will suffer water retention, reducedurine flow and an accumulation of waste toxins in the blood and body.These conditions result from reduced renal function or renal failure(kidney failure) and are believed to increase the workload of the heart.In a CHF patient, renal failure will cause the heart to furtherdeteriorate as fluids are retained and blood toxins accumulate due tothe poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. Such high levels of renal sympathetic nerve activity lead todecreased removal of water and sodium from the body, as well asincreased secretion of renin. Increased renin secretion leads tovasoconstriction of blood vessels supplying the kidneys which causesdecreased renal blood flow. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have previously described methods and apparatus for treatingrenal disorders by applying a pulsed electric field to neural fibersthat contribute to renal function. See, for example, Applicants'co-pending U.S. patent applications Ser. No. 11/129,765, filed on May13, 2005, and Ser. No. 11/189,563, filed on Jul. 25, 2005, both of whichare incorporated herein by reference in their entireties. A pulsedelectric field (“PEF”) may initiate denervation or other renalneuromodulation via irreversible electroporation, electrofusion or otherprocesses. The PEF may be delivered from apparatus positionedintravascularly, extravascularly, intra-to-extravascularly or acombination thereof. Additional methods and apparatus for achievingrenal neuromodulation via localized drug delivery (such as by a drugpump or infusion catheter), a stimulation electric field, or othermodalities are described, for example, in co-owned and co-pending U.S.patent application Ser. No. 10/408,665, filed Apr. 8, 2003, and U.S.Pat. No. 6,978,174, both of which are incorporated herein by referencein their entireties.

Electrofusion generally refers to the fusion of neighboring cellsinduced by exposure to an electric field. Contact between targetneighboring cells for the purposes of electrofusion may be achieved in avariety of ways, including, for example, via dielectrophoresis. Intissue, the target cells may already be in contact, thus facilitatingelectrofusion.

Electroporation and electropermeabilization generally refer to methodsof manipulating the cell membrane or intracellular apparatus. Forexample, the porosity of a cell membrane may be increased by inducing asufficient voltage across the cell membrane through short, high-voltagepulses. The extent of porosity in the cell membrane (e.g., size andnumber of pores) and the duration of effect (e.g., temporary orpermanent) are a function of multiple variables, such as the fieldstrength, pulse width, duty cycle, electric field orientation, cell typeor size and/or other parameters.

Cell membrane pores will generally close spontaneously upon terminationof relatively lower strength electric fields or relatively shorter pulsewidths (herein defined as “reversible electroporation”). However, eachcell or cell type has a critical threshold above which pores do notclose such that pore formation is no longer reversible; this result isdefined as “irreversible electroporation,” “irreversible breakdown” or“irreversible damage.” At this point, the cell membrane ruptures and/orirreversible chemical imbalances caused by the high porosity occur. Suchhigh porosity can be the result of a single large hole and/or aplurality of smaller holes.

A potential challenge of using intravascular PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of PEF therapy may persistently injure therenal vasculature, but an overly conservative course of PEF therapy maynot achieve the desired renal neuromodulation.

Applicants have previously described methods and apparatus formonitoring tissue impedance or conductivity to determine the effects ofpulsed electric field therapy, e.g., to determine an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, which is incorporated herein by reference in itsentirety. Pulsed electric field electroporation of tissue causes adecrease in tissue impedance and an increase in tissue conductivity. Ifinduced electroporation is reversible, tissue impedance and conductivityshould approximate baseline levels upon cessation of the pulsed electricfield. However, if electroporation is irreversible, impedance andconductivity changes should persist after terminating the pulsedelectric field. Thus, monitoring the impedance or conductivity of targetand/or non-target tissue may be utilized to determine the onset ofelectroporation and to determine the type or extent of electroporation.Furthermore, monitoring data may be used in one or more manual orautomatic feedback loops to control the electroporation.

In view of the foregoing, it would be desirable to provide additionalmethods and apparatus for achieving renal neuromodulation.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic isometric detail view showing the location of therenal nerves relative to the renal artery.

FIGS. 3A and 3B are schematic isometric and end views, respectively,illustrating orienting of an electric field for selectively affectingrenal nerves.

FIG. 4 is a schematic side view, partially in section, illustrating anexample of a multi-vessel method and apparatus for renalneuromodulation.

FIGS. 5A and 5B are schematic side views, partially in section,illustrating other examples of multi-vessel methods and apparatus forrenal neuromodulation.

FIG. 6 is a schematic side view, partially in section, illustratinganother method of utilizing the apparatus of FIG. 5A for multi-vesselrenal neuromodulation.

FIGS. 7A and 7B are schematic top views, partially in cross-section,illustrating additional examples of multi-vessel methods and apparatusfor renal neuromodulation.

FIG. 8 is a schematic top view, partially in cross-section, illustratingan embodiment of the apparatus of FIG. 7 for assessing renalcatecholamine spillover.

FIG. 9 is a schematic top view, partially in cross-section, illustratingan example of multi-vessel methods and apparatus for renalneuromodulation comprising overlapping bipolar electric fields.

FIG. 10 is a schematic view illustrating a multi-vessel system for renalneuromodulation configured in accordance with another embodiment of thedisclosure.

DETAILED DESCRIPTION A. Overview

The methods and apparatus of the present invention may be used tomodulate neural fibers that contribute to renal function and may exploitany suitable neuromodulatory techniques that will achieve the desiredneuromodulation. Several embodiments of the present invention aremethods and apparatus for neuromodulation via a pulsed electric field(“PEF”), a stimulation electric field, localized drug delivery, highfrequency ultrasound, thermal techniques, athermal techniques,combinations thereof, and/or other techniques. Neuromodulation may, forexample, effectuate irreversible electroporation or electrofusion,necrosis and/or inducement of apoptosis, alteration of gene expression,action potential blockade or attenuation, changes in cytokineup-regulation and other conditions in target neural fibers. In severalembodiments, neuromodulation is achieved via multi-vessel methods andapparatus with neuromodulatory elements positioned within multiplevessels and/or multiple branches of a single vessel.

In some patients, when the multi-vessel neuromodulatory methods andapparatus of the present invention are applied to renal nerves and/orother neural fibers that contribute to renal neural functions, theapplicants believe that the neuromodulation may directly or indirectlyincrease urine output, decrease plasma renin levels, decrease tissue(e.g., kidney) and/or urine catecholamines, cause renal catecholamine(e.g., norepinephrine) spillover, increase urinary sodium excretion,and/or control blood pressure. Furthermore, applicants believe thatthese or other changes may prevent or treat congestive heart failure,hypertension, acute myocardial infarction, end-stage renal disease,contrast nephropathy, other renal system diseases, and/or other renal orcardio-renal anomalies. The methods and apparatus described herein maybe used to modulate efferent and/or afferent nerve signals.

Renal neuromodulation preferably is performed in a bilateral fashionsuch that neural fibers contributing to renal function of both the rightand left kidneys are modulated. Bilateral renal neuromodulation mayprovide enhanced therapeutic effect in some patients as compared torenal neuromodulation performed unilaterally, i.e. as compared to renalneuromodulation performed on neural tissue innervating a single kidney.In some embodiments, concurrent modulation of neural fibers thatcontribute to both right and left renal function may be achieved; whilein other embodiments, modulation of the right and left neural fibers maybe sequential. Bilateral renal neuromodulation may be continuous orintermittent, as desired.

When utilizing an electric field to achieve desired renalneuromodulation, the electric field parameters may be altered andcombined in any suitable combination. Such parameters can include, butare not limited to, voltage, field strength, frequency, pulse width,pulse duration, the shape of the pulse, the number of pulses and/or theinterval between pulses (e.g., duty cycle), etc. For example, whenutilizing a pulsed electric field, suitable field strengths can be up toabout 10,000 V/cm and suitable pulse widths can be up to about 1 second.Suitable shapes of the pulse waveform include, for example, ACwaveforms, sinusoidal waves, cosine waves, combinations of sine andcosine waves, DC waveforms, DC-shifted AC waveforms, RF waveforms,square waves, trapezoidal waves, exponentially-decaying waves, orcombinations. The field includes at least one pulse, and in manyapplications the field includes a plurality of pulses. Suitable pulseintervals include, for example, intervals less than about 10 seconds.These parameters are provided as suitable examples and in no way shouldbe considered limiting.

To better understand the structures of devices of the present inventionand the methods of using such devices for renal neuromodulation, it isinstructive to examine the renal anatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN generally extending longitudinally along the lengthwisedimension L of renal artery RA, generally within the adventitia of theartery. The renal artery RA has smooth muscle cells SMC that generallysurround the arterial circumference and spiral around the angular axis θof the artery. The smooth muscle cells of the renal artery accordinglyhave a lengthwise or longer dimension extending relatively transverse(i.e., non-parallel) to the lengthwise dimension of the renal artery.The misalignment of the lengthwise dimensions of the renal nerves andthe smooth muscle cells is defined as “cellular misalignment.”

Referring to FIGS. 3A and 3B, the cellular misalignment of the renalnerves and the smooth muscle cells optionally may be exploited toselectively affect renal nerve cells with reduced effect on smoothmuscle cells. More specifically, because larger cells require a lowerelectric field strength to exceed the cell membrane irreversibilitythreshold voltage or energy for irreversible electroporation,embodiments of the present invention optionally may be configured toalign at least a portion of an electric field with or near the longerdimensions of the cells to be affected. In specific embodiments, thedevice has a bipolar electrode pair positioned in different vessels andconfigured to create an electrical field aligned with or near thelengthwise dimension L of the renal artery RA to preferentially affectthe renal nerves RN. By aligning an electric field so that the fieldpreferentially aligns with the lengthwise aspect of the cell rather thanthe diametric or radial aspect of the cell, lower field strengths may beused to affect target neural cells, e.g., to necrose or fuse the targetcells, to induce apoptosis, to alter gene expression, to attenuate orblock action potentials, to change cytokine up-regulation and/or toinduce other suitable processes. This is expected to reduce total energydelivered to the system and to mitigate effects on non-target cells inthe electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning a pulsed electric field (“PEF”) with thelengthwise or longer dimensions of the target cells, the PEF maypropagate along the lateral or shorter dimensions of the non-targetcells (i.e., such that the PEF propagates at least partially out ofalignment with non-target smooth muscle cells SMC). Therefore, as seenin FIGS. 3A and 3B, applying a PEF with propagation lines Li generallyaligned with the longitudinal dimension L of the renal artery RA isexpected to preferentially cause electroporation (e.g., irreversibleelectroporation), electrofusion or other neuromodulation in cells of thetarget renal nerves RN without unduly affecting the non-target arterialsmooth muscle cells SMC. The pulsed electric field may propagate in asingle plane along the longitudinal axis of the renal artery, or maypropagate in the longitudinal direction along any angular segment θthrough a range of 0°-360°.

A PEF system placed within and/or in proximity to the wall of the renalartery may propagate an electric field having a longitudinal portionthat is aligned to run with the longitudinal dimension of the artery inthe region of the renal nerves RN and the smooth muscle cells SMC of thevessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed, fused orotherwise affected. Monitoring elements optionally may be utilized toassess an extent of, e.g., electroporation, induced in renal nervesand/or in smooth muscle cells, as well as to adjust PEF parameters toachieve a desired effect.

C. Embodiments of Systems and Methods for Multi-Vessel Neuromodulation

With reference to FIGS. 4-7, examples of multi-vessel PEF systems andmethods are described. FIG. 4 shows one embodiment of a multi-vesselpulsed electric field apparatus 100 that includes multiple electrodes110 configured to deliver a pulsed electric field to renal neural fibersto achieve renal neuromodulation. The electrodes 110 are positionedintravascularly within multiple vessels that branch off from main renalartery RA. The apparatus 100 may further comprise a catheter 102 throughwhich the electrodes 110 may be delivered to vessel branchings. Thecatheter also may comprise a positioning element 104, as describedhereinafter. Applicants have previously described intravascular PEFsystems, for example, in co-pending U.S. patent application Ser. No.11/129,765, filed May 13, 2005, which has been incorporated herein byreference in its entirety.

The proximal section of the apparatus 100 generally has one or moreelectrical connectors to couple the electrodes 110 to a pulse generator101. The pulse generator is located external to the patient. Thegenerator, as well as any of the electrode embodiments described herein,may be utilized with any embodiment of the present invention describedhereinafter for delivery of a PEF with desired field parameters. Itshould be understood that electrodes of embodiments describedhereinafter may be electronically connected to the generator even thoughthe generator is not explicitly shown or described with each embodiment.

As seen in FIG. 4, the electrodes 110 are positioned in multiple vesselsthat branch off from a renal artery RA in the vicinity of a kidney K.The electrical signals may be applied independently and/or dynamicallyto each of the electrodes 110 to facilitate a monopolar and/or a bipolarenergy delivery between/among any of the electrodes and/or an externalground pad (not shown). A ground pad, for example, may be attachedexternally to the patient's skin (e.g., to the patient's leg, flank,back or side) when one or more of the electrodes deliver monopolarenergy. Additionally or alternatively, the optional ground pad may beattached externally to the patient adjacent to the targeted kidney toinduce desired directionality in a monopolar electrical field. Acombination bipolar and monopolar PEF treatment may be more effectivethan a stand-alone bipolar and/or a stand-alone monopolar treatment forsome patients or for some indications.

It is expected that applying a bipolar field between a desired pair ofthe electrodes 110 positioned in different vessels, e.g., between theelectrode 110 a and the electrode 110 b, may modulate the function ofthe target neural fibers in a manner that at least partially denervatesthe patient's kidney. The electrodes 110 a and 110 b (as well as theelectrodes 110 b and 110 c) optionally may be laterally spaced from oneanother along the lengthwise dimension of the renal artery RA, which isexpected to preferentially align an electric field delivered between theelectrodes with the target neural fibers. The neuromodulation may beachieved thermally or substantially athermally. Such PEF therapy mayalleviate clinical symptoms of CHF, hypertension, renal disease,myocardial infarction, contrast nephropathy and/or other renal orcardio-renal diseases for a period of months (e.g., potentially up tosix months or more). This time period may be sufficient to allow thebody to heal to potentially reduce the risk of CHF onset after an acutemyocardial infarction and mitigate the need for subsequent re-treatment.Alternatively, as symptoms reoccur, or at regularly scheduled intervals,the patient can return to the physician for a repeat therapy.

The effectiveness of the initial therapy, and thus the potential needfor repeating the therapy, can be evaluated by monitoring severaldifferent physiologic parameters. For example, plasma renin levels,renal catecholamine (e.g., norepinephrine) spillover, urinecatecholamines, or other neurohormones that are indicative of increasedsympathetic nervous activity can provide an indication of the extent ofdenervation. Additionally or alternatively, a nuclear imaging test, suchas a test utilizing 131-Iodine metaiodobenzylguanidine (“MIBG”), may beperformed to measure a degree of adrenergic innervation. As anotheroption, imaging may be performed with Technetium-99mmercaptoacetylglycine (“Tc-99m MAG3”) to evaluate renal function.Alternatively, provocative maneuvers known to increase sympatheticnervous activity, such as head-out water immersion testing, may beconducted to determine the need for repeat therapy.

Embodiments of the PEF system 100 optionally may comprise one or morepositioning elements for centering or otherwise positioning the systemor parts of the system within the patient's vasculature. The positioningelement may, for example, comprise inflatable balloons and/or expandablewire baskets or cages. The positioning element optionally may comprisean impedance-altering element configured to alter impedance within thepatient's vasculature to better direct an applied electric field acrossthe vessel wall to target neural fibers. When the positioning element isa balloon, it may temporarily block blood flow and thereby alter theimpedance within the patient's vessel. Additionally or alternatively,the positioning element may further comprise one or more electrodes. Inone embodiment, a balloon positioning element has a conductive exteriorand/or is fabricated from a conductive polymer that may be used as anelectrode in a multi-vessel PEF system.

In FIG. 4, the PEF system 100 comprises an expandable positioningelement 104 coupled to the catheter 102. The positioning element 104 isconfigured for delivery and retrieval from a treatment site in a reducedprofile delivery configuration, and for expansion at the treatment siteto the deployed configuration of FIG. 4. With the positioning element inthe fully expanded, deployed configuration of FIG. 4, impedancecharacteristics within the renal artery RA may be altered, and/ordelivery and retrieval of the electrode(s) 110 to the multiple vesselbranchings may be facilitated.

As discussed previously, it is expected that a multi-vessel PEF therapymay effectuate one or more of the following: irreversibleelectroporation or electrofusion; necrosis and/or inducement ofapoptosis; alteration of gene expression; action potential blockade orattenuation; changes in cytokine up-regulation; and other conditions intarget neural fibers. In some patients, when such neuromodulatorymethods and apparatus are applied to renal nerves and/or other neuralfibers that contribute to renal neural functions, applicants believethat the neuromodulation may at least partially denervate the patient'skidney(s). This may result in increased urine output, decreased plasmarenin levels, decreased tissue (e.g., kidney) and/or urinecatecholamines, renal catecholamine (e.g., norepinephrine) spillover,increased urinary sodium excretion, and/or controlled blood pressure.Furthermore, applicants believe that these or other changes may preventor treat congestive heart failure, hypertension, myocardial infarction,renal disease, contrast nephropathy, other renal system diseases, and/orother renal or cardio-renal anomalies for a period of months (e.g.,potentially up to six months or more).

The methods and apparatus described herein could be used to modulateefferent or afferent nerve signals, as well as combinations of efferentand afferent nerve signals. Neuromodulation in accordance with severalembodiments of the present invention can be achieved without completelyphysically severing, i.e., without fully cutting, the target neuralfibers. However, it should be understood that such neuromodulation mayfunctionally achieve results analogous to physically severing the neuralfibers even though the fibers may not be completely physically severed.

The apparatus described herein additionally may be used to quantify theefficacy, extent or cell selectivity of PEF therapy to monitor and/orcontrol the therapy. When a pulsed electric field initiateselectroporation, the impedance of the electroporated tissue begins todecrease and the conductivity of the tissue begins to increase. If theelectroporation is reversible, the electrical parameters of the tissuewill return to baseline values or approximate baseline values afterterminating the PEF. However, if the electroporation is irreversible,the changes in the electrical parameters of the tissue will persistafter terminating the PEF. These phenomena may be utilized to monitorboth the onset and the effects of PEF therapy. For example,electroporation may be monitored directly using conductivitymeasurements or impedance measurements, such as Electrical ImpedanceTomography (“EIT”), electrical impedance or conductivity indices and/orother electrical impedance/conductivity measurements. Suchelectroporation monitoring data optionally may be used in one or morefeedback loops to control delivery of PEF therapy.

In order to collect the desired monitoring data, additional monitoringelectrodes optionally may be provided in proximity to the monitoredtissue. The distance between such monitoring electrodes preferably wouldbe specified prior to therapy delivery and used to determineconductivity from impedance or conductance measurements. For thepurposes of the present invention, the imaginary part of impedance maybe ignored such that impedance is defined as peak voltage divided bypeak current, while conductance may be defined as the inverse ofimpedance (i.e., peak current divided by peak voltage), and conductivitymay be defined as conductance per unit distance. Applicants havepreviously described methods and apparatus for monitoring PEF therapyand have provided illustrative PEF waveforms, for example, in co-pendingU.S. patent application Ser. No. 11/233,814, filed Sep. 23, 2005, whichhas been incorporated herein by reference in its entirety.

Referring now to FIGS. 5A and 5B, additional embodiments of multi-vesselmethods and apparatus for renal neuromodulation are described. The PEFsystem 200 of FIG. 5A comprises a guide catheter 210 through which afirst element 220 having a first electrode 222 and an optionalpositioning element 224, as well as a second element 230 having a secondelectrode 232, may be advanced. The first electrode 222 is positioned ina first vessel that branches off of the renal artery RA and the secondelectrode 232 is positioned within a second vessel or branch of avessel. The positioning element 224 is expanded within the first vesselbranch to center or otherwise position the first electrode 222 withinthe vessel and/or to alter impedance within the vessel. The firstelectrode 222 may, for example, be an active electrode and the secondelectrode 232 may be a return electrode for creating a bipolar electricfield between the electrodes to modulate target neural fibers thatcontribute to renal function. FIG. 5B illustrates an alternativeembodiment in which the first element 220 comprises a catheter having alumen with a side port 226. As shown, the second element 230 may bepositioned in the lumen and may pass through the side port 226 of thefirst element 220 to position the second electrode 232 within a vesselbranching of the renal artery RA. Although a separate guide catheter isnot necessarily required for the embodiment shown in FIG. 5B, the firstelement 220 in FIG. 5B optionally may be advanced into position via aseparate guide catheter, such as the guide catheter 210 of FIG. 5A.

Referring now to FIG. 6, another multi-vessel method of using theapparatus of FIG. 5A for renal neuromodulation is described. In additionto positioning electrodes within multiple branchings of the renal arteryRA, a multi-vessel renal neuromodulation may be achieved with theelectrodes positioned within additional or alternative vessels. In FIG.6, the first element 220 has been advanced through the guide catheter210 to a position within the renal artery RA. The second element 230 hasbeen advanced to a position within the abdominal aorta AA. A bipolarelectrical field may be delivered between the first electrode 222 andthe second electrode 232 to achieve renal neuromodulation.

With reference now to FIGS. 7A and 7B, in addition to placement of theelectrode(s) within (a) the renal artery RA, (b) branchings of the renalartery and/or (c) additional or alternative parts of the patient'sarterial vasculature, multi-vessel renal neuromodulation may be achievedby locating one or more of the electrodes at least partially within thepatient's venous vasculature. In FIG. 7, electrodes are positionedwithin both the renal artery RA and the renal vein RV of the patient.The PEF system 300 can comprise a catheter 310 positioned within therenal artery RA and an element 320 positioned within the renal vein RV.The catheter 310 comprises a first electrode 312 and an optionalpositioning element 314. The catheter 310 may be advanced into positionwithin the renal artery, for example, over a guide wire G, then thepositioning element may be expanded to center or otherwise position theelectrode 312 within the vessel and/or to alter impedance within thevessel. The element 320 comprises a second electrode 330 that can bepositioned within the renal vein, and the element 320 can optionallyinclude a positioning element.

A bipolar electric field may be delivered between the first electrode312 positioned within the renal artery and the second electrode 330positioned within the renal vein to modulate target neural fibers thatcontribute to renal function via a multi-vessel approach. In FIG. 7A,electrodes 312 and 330 are relatively laterally aligned with oneanother. In FIG. 7B, the electrodes are laterally spaced apart from oneanother, which may facilitate preferential alignment of a bipolarelectrical field delivered across the electrodes with the target neuralfibers.

As discussed previously, a renal catecholamine (e.g., norepinephrine)spillover may indicate the extent of denervation or other renalneuromodulation achieved by methods in accordance with the presentinvention. A renal catecholamine spillover is defined as an imbalancebetween an amount of a renal catecholamine entering a kidney via a renalartery and an amount of the renal catecholamine exiting the kidney via arenal vein. For, example, neuromodulation may induce the kidney toexcrete more norepinephrine into the renal vein than that which hadentered the kidney via the renal artery. A baseline measurement of renalcatecholamine spillover may be made prior to the renal neuromodulation.This baseline then may be compared to a measurement of the renalcatecholamine spillover taken after the renal neuromodulation, and thedifference may be attributed to the renal neuromodulation.

In order to measure the renal catecholamine spillover, blood may bedrawn from the patient. For example, blood may be drawn from the renalartery and from the renal vein, and a differential in unit volume of themonitored renal catecholamine(s) between the arterial and venous bloodmay be used to quantify the renal catecholamine spillover and thusassess the degree of the renal neuromodulation. Such blood draws may,for example, be achieved by drawing blood through one or more guidecatheters used to deliver a PEF system, such as the PEF system 300 ofFIG. 7, to the renal artery and the renal vein.

The blood draws additionally or alternatively may be made via one orblood ports integrated into the PEF system. In the embodiment of FIG. 8,the catheter 310 of the PEF system 300 of FIG. 7 comprises an arterialblood port 316 for drawing arterial blood, and the element 320 comprisesa catheter having a venous blood port 322 for drawing venous blood.Additional and alternative methods and apparatus for monitoring of therenal catecholamine spillover will be apparent to those of skill in theart.

In addition to delivery of a bipolar electric field between a firstelectrode positioned within a first vessel or vessel branch, and asecond electrode positioned within a second vessel or vessel branch, abipolar electric field may be delivered between first and secondelectrodes positioned solely within a single vessel or vessel branch. Asseen in FIG. 9, a first bipolar electric field may be delivered betweenelectrodes 312 a and 312 b positioned within a first vessel, such as therenal artery RA, while a second bipolar electric field may be deliveredbetween electrodes 330 a and 330 b positioned within a second vessel,such as the renal vein RV. The first and second bipolar electric fieldsmay be delivered in a manner that creates a zone of overlap Z betweenthe bipolar fields.

Tissue positioned within the overlap zone Z may exhibit locally enhancedintensity of an induced electric field within the tissue, as compared tothe intensity within tissue positioned outside of the overlap zone. Whena target neural fiber, such as a target renal neural fiber RN, passesthrough the overlap zone Z, the locally enhanced intensity of theinduced electric field within the target neural fiber may be of amagnitude sufficient to desirably modulate the neural fiber.Furthermore, the intensity of induced electric fields outside of theoverlap zone desirably may be of magnitudes insufficient to cause damageto non-target tissues. Overlapping electric fields thus may reduce arisk of undesirable damage to non-target tissues, while locallyproviding an induced electric field of sufficient magnitude to achievedesired renal neuromodulation. Although preferred illustrativevariations of the present invention are described above, it will beapparent to those skilled in the art that various changes andmodifications may be made thereto without departing from the invention.For example, one or more electrodes may be positioned in other parts ofthe patient's venous vasculature, such as within the patient's inferiorvena cava or within vessel branchings of the patient's renal vein. It isintended in the appended claims to cover all such changes andmodifications that fall within the true spirit and scope of theinvention.

We claim:
 1. A method for performing renal denervation, the methodcomprising: positioning a catheter within a renal artery of a humanpatient and proximate to renal nerves of the patient; intravascularlypositioning a first electrode carried by the catheter within a firstvessel branching from the renal artery; intravascularly positioning asecond electrode carried by the catheter within a second vesselbranching from the renal artery, wherein the second vessel is differentthan the first vessel; and thermally modulating a function of the renalnerves via radio frequency (RF) energy from the first and secondelectrodes.
 2. The method of claim 1 wherein intravascularly positioningthe first electrode within the first vessel occurs beforeintravascularly positioning the second electrode within the secondvessel.
 3. The method of claim 1 wherein intravascularly positioning thefirst electrode within the first vessel and intravascularly positioningthe second electrode within the second vessel occur simultaneously orapproximately simultaneously.
 4. The method of claim 1, furthercomprising monitoring a parameter of the catheter, the first and secondelectrodes, and/or tissue proximate the renal nerves during therapy. 5.The method of claim 4, further comprising adjusting therapy in responseto the monitored parameter.
 6. The method of claim 4, further comprisingaltering delivery of the RF energy from the first electrode and/or thesecond electrode in response to the monitored parameter.
 7. The methodof claim 1 wherein thermally modulating a function of the renal nervescomprises modulating at least one of afferent and efferent signals alongthe renal nerves.
 8. The method of claim 1 wherein thermally modulatinga function of the renal nerves results in a therapeutically beneficialreduction in blood pressure in the patient.